Trauma accounts for thousands of deaths each year. Hemorrhagic shock is an important etiologic factor in trauma-related morbidity and mortality. Along with head injuries, it accounts for the majority of deaths that occur within 24 hours of an accident. Hemorrhagic shock also contributes to the development of multiple organ failure (MOF) syndrome that is responsible for a large proportion of late deaths. Liver dysfunction secondary to hemorrhagic shock has been recognized as clinical entity for over 60 years, is a component of MOF, and is associated with an extremely high mortality. The basic etiologic mechanisms responsible for hepatic dysfunction after hemorrhagic shock are largely unknown and, since there are no effective therapeutic strategies, care is supportive. We hypothesize that specific, identifiable cellular changes occur at the molecular level following hemorrhagic shock and resuscitation that contribute to hepatic dysfunction and injury. Our preliminary data demonstrate that nitric oxide (NO) synthesis is an important protective pathway in modifying shock-induced hepatic injury. We hypothesize that this beneficial effect in hemorrhagic shock is due to the regulation of hepatic function by NO in two essential areas. First, we hypothesize that NO is essential in regulating hepatic circulatory function during hock and this will predominantly be due to the actions of the constitutive nitric oxide synthase (NOS) in endothelial cells ecNOS). Secondly, we hypothesize that NO regulates the expression and activity of specific genes and their products in hepatocytes that enable the hepatocyte to withstand shock- induced cellular stress. We predict the latter function will be due chiefly to the actions of the inducible NOS (iNOS) in hepatocytes. In Aim I of this proposal, we will characterize the contribution of ecNOS and iNOS in preventing hemorrhagic shock-induced hepatic injury. In Aim II, we will determine the role of NO in regulating hepatic perfusion in hemorrhagic shock and its contribution to the development of hepatic dysfunction and injury. We will also examine the interaction between NO and neutrophils, platelets, and oxygen radicals and their effects on sinusoidal perfusion. In Aim III, we will determine the role of NO in regulating intracellular pathways f the hepatocyte that are important in shock-induced hepatic injury and hepatic dysfunction. We will specifically examine the role of NO in the expression of NOS, heat shock proteins, and heme oxygenase. We expect that our results will show at NO is an essential component in the response of the liver to shock-induced stress. We predict that both ecNOS and iNOS will have protective functions in regulating hepatic function and physiology after hemorrhagic shock.